TRα inhibits arterial renin-angiotensin system expression and prevents cholesterol accumulation in vascular smooth muscle cells

Ann Endocrinol (Paris). 2019 Apr;80(2):89-95. doi: 10.1016/j.ando.2018.09.008. Epub 2018 Sep 25.

Abstract

Objectives: The tissue renin-angiotensin system (tRAS) plays a key role in the maintenance of cellular homeostasis but is also implicated in atherosclerosis. Thyroid hormone (TH) contributes, via genomic effects, to control of tRAS gene expression in the arterial wall and vascular smooth muscle cells (VSMCs). We investigated the specific functions of TH receptors-α and -β (TRα and TRβ) on tRAS gene expression in the aorta and VSMCs, and the potential protective effect of TRα against atherosclerosis.

Material and methods: Using aorta and cultured aortic VSMCs from TRα and TRβ deficient mice, tRAS gene expression was analyzed by determining mRNA levels on real-time PCR. Gene regulation under cholesterol loading mimicking atherosclerosis conditions was also examined in VSMCs in vitro.

Results: TRα deletion significantly increased expression of angiotensinogen (AGT) and angiotensin II receptor type 1 subtype a (AT1Ra) at transcriptional level in aorta, a tissue with high TRα expression level. TRα activity thus seems to be required for maintenance of physiological levels of AGTand AT1Raexpression in the arterial wall. In addition, during cholesterol loading, TRα deletion significantly increased cholesterol content in VSMCs, with a weaker decrease in AGTexpression.

Conclusion: TRα seems to have an inhibitory impact on AGTand AT1Raexpression, and loss of TRα function in TRα0/0 mice increases tRAS expression in the aortic wall. More importantly, TRα deletion significantly increases VSMC cholesterol content. Our results are consistent with a protective role of TRα against atherosclerosis.

Keywords: Atherosclerosis; Athérosclérose; Cellules musculaires lisses vasculaires; Récepteur d’hormone thyroïdienne-α; Récepteur d’hormone thyroïdienne-β; Système rénine-angiotensine tissulaire; Thyroid hormone receptor-α; Thyroid hormone receptor-β; Tissue renin-angiotensin system; Vascular smooth muscle cells.

MeSH terms

  • Animals
  • Arteries / metabolism*
  • Arteries / pathology
  • Atherosclerosis / drug therapy
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Gene Expression Regulation / drug effects
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / genetics*
  • Thyroid Hormone Receptors alpha / agonists
  • Thyroid Hormone Receptors alpha / genetics
  • Thyroid Hormone Receptors alpha / physiology*
  • Thyroid Hormones / pharmacology

Substances

  • Thyroid Hormone Receptors alpha
  • Thyroid Hormones
  • Cholesterol